RT Journal Article
SR Electronic
T1 Transcytosis maintains CFTR apical polarity in the face of constitutive and mutation-induced basolateral missorting
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 411322
DO 10.1101/411322
A1 Aurélien Bidaud-Meynard
A1 Florian Bossard
A1 Andrea Schnúr
A1 Ryosuke Fukuda
A1 Guido Veit
A1 Haijin Xu
A1 Gergely L. Lukacs
YR 2018
UL http://biorxiv.org/content/early/2018/09/07/411322.abstract
AB Apical polarity of cystic fibrosis transmembrane conductance regulator (CFTR) is essential for solute and water transport in secretory epithelia and can be impaired in human diseases. Maintenance of apical polarity in the face of CFTR non-polarized delivery and compromised apical retention of mutant CFTRs lacking PDZ-domain protein (NHERF1) interaction, remains enigmatic. Here we show that basolateral CFTR delivery originates from biosynthetic (∼35%) and endocytic (∼65%) recycling missorting. Basolateral channels are retrieved via basolateral-to-apical transcytosis, enhancing CFTR apical expression by two-fold and suppressing its degradation. CFTR transcytosis is microtubule-dependent but independent of Myo5B-, Rab11- and NHERF1 binding to its C-terminal DTRL motif in airway epithelia. Increased basolateral delivery due to compromised apical recycling and accelerated internalization upon impaired NHERF1-CFTR association is largely counterbalanced by CFTR efficient basolateral internalization and apical transcytosis. Thus, transcytosis represents a previously unrecognized but indispensable mechanism for maintaining CFTR apical polarity by attenuating its constitutive and mutation-induced basolateral missorting.